Efficient synthesis of substituted 3-amino-benzonitriles via continuous flow nucleophilic aromatic substitution

ORGN 637

Tamás Nagy, tamas.nagy@thalesnano.com, László Lengyel, Attila Wootsch, György Dormán, László Ürge, Ferenc Darvas, and Richard Jones. ThalesNano Inc, H-1031 Záhony u. 7, Budapest, Hungary
Heteroaromatic or aromatic ring precursors with 2-3 identical functionalities are often used in sequential derivatization relying on the reactivity difference or the selective execution of the reaction such as nucleophilic aromatic substitution. The real challenge in this approach is to achieve successive derivatization selectively even if the reactivities are comparable. The major advantages of continuous flow chemistry are the rapid parameter optimization which ensures selectivity as well as the enhanced parameter space (pressure, temperature). We studied the synthesis of a 3-amino-benzonitrile core which is a privileged motif in medicinal chemistry. The key step in the synthesis is the selective fluoro- amine exchange reaction in the presence of another fluoro functionality. This reaction was realized in a novel high pressure, high temperature flow reactor (ThalesNano Inc.) with 100 % conversion and selectivity (T=200-275°C, P=200bar). The presentation will describe the optimization process together with further examples of substituted 3-amino-benzonitrile derivatives.